Process for preparing benzophenone compounds



United States Patent 3,113,970 PRQCESS FOR PREPARING BENZOPHENONECOMPOUNDS Harry L. Slates, Florham Park, and Norman L. Wendler, Summit,N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of NewJersey N0 Drawing. Filed Nov. 22, 1960, Ser. No. 70,912 2 Claims. (Cl.260-591) 1 This invention relates generally to the preparation ofchemical compounds. More particularly, it relates to a i new and novelsynthesis of griseofulvin and related 3,113,970 Patented Dec. 10, 1963"ice while, efforts have continued to synthesize the complexgriseofulvin molecule chemically since a feasible chemical synthesiswould permit the study of improved methods of making griseofulvin andwould further permit the preparation of griseofulvin analogs andderivatives that are not accessible by fermentation.

It has now been found that griseofulvin and analogs thereof may besynthesized chemically by a relatively short and feasible processemploying as the starting materials an appropriately substituted phenoland an appropriately substituted benzoyl halide. This process may bepictured structurally as follows:

the structural formula OCH: 0

i a 00in I H3C0 \O on; 01

It is an antifungal agent effective when administered orally in thetreatment of various systemic fungus infections. Heretofore,griseofulvin has been produced microbiologically by certain strains ofPenicillia. Mean- O I HaCO \O OCH3 OCH;

In the above formulas, R may be hydrogen or halogen, R may be hydrogenor a lower alkyl group, X is chlorine or bromine, and Y is a loweralkanoyl radical.

As set forth in the flow diagram, it has been found that2,4'-dihydroxy-3-R-4,6,2'-trimethoxy 6 R -benzophenone (Compound IIIabove), an important intermediate in the overall synthesis, may beobtained by reacting together 2-R -4-acetoxy-6-methoxy benzoyl chlorideand 2-R-3,5-dimethoxyphenol to produce 2-R-3,5- dimethoXy-2R -4 acetoxy6 methoxybenzoate (Compound I), treating this latter compound with abase under mild conditions to form 2-R-3,5-dimethoxy-2-R-4-hydroxy-6-methoxybenzoate (Compound II), and then exposing thislast-mentioned substance to ultra-violet light whereby the benzophenoneIII is produced. In the above compounds R and R have the meanings setforth previously.

The 2,4'-dihydroXy-3-R-4,6,2'-trimethoxy-6-R -benzophenone (III) formedas described above is converted on treatment with potassium ferricyanidein aqueous potassium carbonate to racernic 7-R-4,6,2'-trimethoxy-6'- R-gris-2',5-diene-3,4-dione (Compound IV), where R and R are as definedabove. The nomenclature used for describing Compounds IV and V is thatrecommended by Grove et al., J. Chem. Soc. 3977 (1952). There may beobtained in this fashion racemic forms of 7-chloro-4, 6,2-trirrethoxy-6'-methyl-gris-2,5-diene-3,4s-dione (dehydrogriseofulvin);7-fiuoro-4,6,2-trimethox -6-methylgris-2',5'-diene-3,4'-dione;4,6,2-trimethoxy 6 methylgris-2',5'-diene-3,4-dione; 7 chloro 4,6,2trimethoxygris-2,5-diene-3,4'-dione; 7-chloro-4,6,2-trimethoxy 6'-ethyl-gris-Z,5'-diene-3,4-dione; 7-chloro-4,6,2trim-ethoxy-6-propyl-gris2,5'-diene-3,4-dione and similar compoundswherein the 7-position may be substituted with hydrogen or halogen, andthe 6-substituent may be hydrogen or a lower alkyl group. 7

One of'the diificulties encountered in the attempts at a total chemicalsynthesis of griseofulvin and analogs thereof has been the reduction ofone of the double bonds in the diene 1V. Successful reduction of theproper double bond would afford racemic griseofulvin (Compound .V, R=Cl,R =CH andracemic analogs of griseofulvin. The one reported method ofeffecting this reduction suffers the disadvantage of requiring anunusual and expensive catalyst. It is one object of the presentinvention to provide a convenient and practical method of bringing aboutthis reduction. A more specific object is provision of a method whichgives high yields of the desired compound without the necessity of usingexpensive and unusual reducing agents. Other objects will be apparentfrom the following description of our invention.

We have now discovered, according to the present invention, that7-R-4,6,2'-trimethoxy-6'R -gris-2,5-diene- 3,4'-dione may be reduced insubstantial yield to the desired 7-R-4,6,2-trimethoxy-6'-R-gris-2 ene3,4 dione (Compound V) by treatment with hydrogen in the presence of apalladium catalyst.

We accomplish our catalytic reduction by bringing together a solution ofthe diene IV in a suitable organic solvent, such as ethyl acetate, and apalladium catalyst, and exposing this reaction mixture tohydrogen. Thehydrogenation is conveniently carried out at about room temperature andsubstantially at atmospheric pressure. It will be appreciated that thereaction may be conducted at higher tempenatures or under a slightpositive pressure,

but these conditions are unnecessary for good yield. As

catalyst it is preferred to employ palladium on charcoal, although othercatalyst carriers could be utilized if desired. With respect to thequantity of catalyst, We prefer to use an amount of palladium equal toabout 25% by weight of the diene 1V, although good results are obtainedwith smaller or larger quantities.

The hydrogenation isallowed to continue until one mole ofhydrogen isconsumed per mole of diene IV. This occurs rapidly although the ratedepends to some extent on the amount of catalyst that is present. Whenthe reaction is complete the reduced product may be convenientlyrecovered by removing the catalyst and reaction solvent, and purifyingthe material by techniques such as chromatography. The methods preferredfor recovering the desired substances from the reaction mixture willdepend, of course, on factors such as the degree of purificaabove, theremay be produced the racemic form of griseol fulvin (Compound V, R=Cl, R=CH and racemates of griseofulvin analogs such as7-fiuoro-4,6,2trimethoxy- 6-methyl-gris-2'-ene-3,4-dione (V, R F, R =CH7- chloro-4,6,2'-trimethoxy-6-ethyl'gris-2'-ene-3,4-dione (V, R CI, R CH J and 4,6,2trimethoxy-gris-2-ene-3,4- dione (V, R=R :H).

' According to a second aspect of this invention, we have discoveredthat 7R-4,6,2'-trimethoxy-6-R -gris-2',5-diene-3,4'-dione (Compound IV)having Formula IV above, where R and R are as previously defined, may beconverted to 2,4'-dihydroxy-3R-4,6,2-trimethoxy-6'-R -benzophenone(Compound III) by treatment with a metallic reducing agent such as witha chromous salt, e.g. chromous chloride, chromous acetate and the like,or with a zinc-acid system such as zinc-acetic acid or zinc-hydrochloricacid. The process may be satisfactorily brought about by intimatelycontacting the diene IV and the reducing agent at room temperature,although elevated temperatures may be used if desired. It issubstantially complete in from about 6 to about 20 hours. Since. it isknown that 7-R-4,6,2-trimethoxy-6'-R -gris-2'-ene-3,4' dione (CompoundV) may be dehydrogenated to 7-R- 4,6,2-trimethoxy-6'-R-gris-2,5-diene-3,4-dione (Compound IV) with selenium dioxide (thismethod has been used for preparing dehydrogriseofulvin from naturalgriseofulvin), our novel synthesis of the substituted benzophenone (Ill)from the diene (IV) permits the ready preparation of the 'benzophenone'from natural griseofulvin. This is of moment because Compound II-I canbe chemically modified without totally destroying the molecule morereadily than Compounds IV and V. There is thus made available a newmethod for preparing griseofulvin analogs from natural griseofulvin.This method comprises the synthesis of Compound III (R Cl, {q -CH fromgriseofulvin via the selenium dioxide and chromous chloride reactionsdescribed above, chemical modification of the benzophenone III asdesired (cg.

removal of the chloro substituent), and re-synthesis of a griseofulvinanalog by the previously discussed potassium ferricyanide and catalytichydrogenation steps.

The following examples are given for the purposes of illustration andnot by way of limitation:

EXAMPLE I A solution of 800 mg. of 2-rnethyl-4-acetoxy-6-methoxybenzoicacid in 20 ml. of thionyl chloride is kept at 50 C. for 2 hours. Thereaction mixture is concentrated to dryness under vacuum to give aresidue of 2-methyl-4- acetoxy-6-methoxybenzoyl chloride. To thisproduct is added 626 mg. of 2-chloro-3,S-dimethoxyphenol and 11 ml. ofpyridine. The mixture is warmed on the steam bath for 2 minutes and thenkept at 25 C. for 18 hours. Chloroform is then added and the mixtureextracted with cold dilute hydrochloric acid, cold dilute sodiumhydroxide solution and saturated sodium chloride solution. Thechloroform solution is dried over magnesium sulfate, filtered and thenconcentrated to dryness under vacuum. Crystallization of the resultingresidue from other gives 880 mg. of2-chloro-3,5-dimethoxyphenyl-2-methyl-4-acetoXy-6-methoxybenzoate, M.P.152-155 C.

)MeoH 281 mu (6, 4150); Nix, 5.75, 5.80

B. 2-Chl0r0-3, 5 -Dimeth0xy phenyl-Z-M ethy l-4-. H ydroxy-o -M ethoxybenzoate dried over magnesium sulfate. It is filtered to remove thedrying agent and concentrated to dryness under vacuum. The residue iscrystallized to give 615 mg. of 2-chlor-3,S-dimethoxyphenyl-Z-methyl-4-hydroxy-6 methoxybenzoate, M.P.142l44 C.;

AMeOH EXAMPLE 2 2,4-Dilzydroxy-3-"hlore-4,6,2'-Trimeth0xy-6- Methylbenzophenone A solution of 100 mg. of 2-chloro-3,5-dimethoxyphenyl2 methyl 4 hydroxy 6 methoxybenzoate in 2.5 ml. of ethanol in a quartztube is irradiated with ultra-violet light (Hanovia Type 16A13 broadspectrum low pressure light source) at 40 C. for 66 hours. The solventis removed and the residue chromatographed on a column of 20 g. ofFlorisil. The column is eluted successively with benzene,benzene-chloroform, chloroform and chloroform-methanol mixtures.Crystallization of the residues obtained from the chloroform: 5-10%methanol eluates from ethyl ether gives 2,4-dihydroxy-3-chloro-4,6,2-trimethoxy-6-methylbenzophenone, M.P. 212.5-215" C.

EXAMPLE 3 Dehydrogriseofulvin To a stirred solution of 2.25 g. of2,4'-dihydroxy- 4,6,2 trimethoxy-6'-methyl-3-chloro-benzophen0ne and 27g. of potassium carbonate in 250 ml. of boiled nitrogen-flusheddistilled water is added a solution of 4.0 g. of potassium ferricyanidein 50 ml. of water. The addition is carried out in a nitrogen atmosphereover a period of 1 hour. The reaction mixture is stirred at roomtemperature under nitrogen for 18 hours. The precipitated material isrecovered by filtration and air dried. It is dissolved in chloroform andthe solution filtered. The chloroform is diluted with about an equalvolume of ether and washed with ice-cold 2% potassium hydroxide solutionand with Water. The organic solvent solution is dried over magnesiumsulfate, filtered and concentrated to dryness in vacuo. The residue iscrystallized from acetone-ethyl acetate to afford substantially pureracemic dehydrogriseofulvin, M.P. 284-286 C.; A max. 292 mu (6, 32,000),infi. 230 m (6, 22,000), infl. 318 (e, 5,900). Further purification bypassage through a Florisil column raises the melting point to 291-293 C.

EXAMPLE 4 Griseofulvin 500 mg. of racemic dehydrogriseofulvin in 110 ml.of ethyl acetate is added to a stirred suspension of 1.0 g. ofpre-reduced 10% palladium on charcoal catalyst and hydrogenated atatmospheric pressure and 22 C. When 10 mole of hydrogen is absorbed(occurs rapidly) the catalyst is removed by filtration and the filtrateconcentrated in vacuo to a viscous pale yellow oil. This oil isdissolved in 50 ml. of methylene chloride and the solution washed with 3x 10 ml. of ice-cold 2% potassium hydroxide, water, and dried overmagnesium sulfate. The methylene chloride solution is filtered andconcentrated to dryness in vacuo. The solid residue thus obtained isdissolved in ml. of benzene and chromatographed on a column of '15 g. ofFlorisil. The column is eluted with l5-ml. portions of benzene,benzene-chloroform mixtures and finally with chloroform. From thechloroform eluates there is obtained two racemates, one with M.P.213-215 C. (11.5% yield) and the second with M.P. ZZZ-224 C. (51%yield). Characterization is by in vivo bio-assay by the disc-platemethod with Botrytis allii as the test organism.

The material melting at 222-224" C. is racemic 6 griseofulvin. It has50% of the activity of natural griseofulvin.

EXAMPLE 5 Z-Chloro-3,5-Dimethoxyphenyl-4-Hydroxy-6- Methoxybenzoate A. 1g. of 4-acetoxy-2-methoxybenzoic acid is added to 20 g. of thionylchloride and the resulting mixture held at 50 C. for minutes. Thereaction mixture is then concentrated to dryness to give a residue of 4-acetoxy-Z-rnethoxybenzoyl chloride. This material is mixed With 15 ml.of pyridine and 720 mg. of 2-chloro- 3,5-dimethoxyphenol. The reactionmixture is heated at about 90 C. for 2 minutes and then held at roomtemperature for 12 hours. Chloroform is then added to the solution and2-chloro-3,5-dimethoxyphenyl-4-acetoxy-6- methoxybenzoate recovered andcrystallized by the procedure described in Example 1A.

The benzoate ester is treated with aqueous methanolic sodium hydroxideat room temperature by the process of Example 113. There is thusobtained 2-chloro-3,5-dimethoxy 4 hydroxy 6 methoxybenzoate, M.P. 147-150 C.;

B. The acid chloride of 2-methyl-4-acetoxy-6-methoxy-benzoic acid isprepared from the free acid as described in Examples 1A and 5A, andreacted with phloroglucinol dimethyl other by the procedure of Example1A to give 3,5-dimethoxyphenyl-Z-methyl-4-acetoxy-6- methoxybenzoate.This ester is hydrolyzed to 3,5-dimethoxyphenyl 2methyl-4-hydroxy-6-meth-oxybenzoate with methanolic sodium hydroxideaccording to the procedures of Examples 1B and 5A.

EXAMPLE 6 Z,4-Dihydr0xy-3-ChZora-4,6,2'-Trimethoxybenzophenone A. 200mg. of 2-chloro-3,5-dimethoxy-4-hydroxy-6- methoxybenzoate in 5 ml. ofethanol in a quartz tube is irradiated with ultra-violet light (HanoviaType 16A13 broad spectrum low pressure light source) at 40 C. for 58hours. The resulting reaction mixture is treated by the recoveryprocedure of Example 2 above to give 2,4-dihydroxy-3-chloro-4,6,2'-trimethoxyhenzophenone.

B. When the above procedure is carried out using 3,5-dimethoxyphenyl 2methyl-4-hydroxy-6-methoxybenzoate as starting material, there isobtained 2,4'-dihydroxy-4,6,2'-trimethoxy-6'-methylbenzophenone.

EXAMPLE 7 7 -Chl0r0-4,6,2'-T rimethoxy-Gris-2,5 -Diene-3,4 '-Di0ne A.2.2 g. of 2,4'-dihydroxy-3-chloro-4,6,2'-trimethoxybenzophenone istreated with 27 g. of potassium carbonate and 4 g. of potassiumferricyanide under nitrogen by the method of Example 3. There isobtained substantially pure racemic 7-chloro-4-6,2'-dirnethoxy-gris-2'5-diene-3,4-dione.

B. When the procedure of Example 3 is carried out employing2,4'-dihydroxy-4,6,2'-trimethoxy 6" methylbenzophenone as the startingmaterial, there is obtained racemic 4,6,2 trimethoxy 6 methyl gris 2,5diene- 3,4'-dione.

EXAMPLE 8 7-Chlor0-4,6,2-Trimethoxy-Gris-2'-Ene3,4'-Di0ne A. When theproduct of Example 7A is treated with hydrogen in the presence ofpalladium on charcoal catalyst according to the procedure of Example 4,there is obtained from the chloroform eluates racemic 7-chloro-4,6,2-trirnethoxy-gris-2'-ene-3,4-dione.

B. When racemic 4,6,2'-trimethoxy-6'-rnethyl-gris-2,5- diene-3,4-dioneis hydrogenated according to the procedure of Example 4, there isobtained racemic 4,6,2- trimethoxy-6-metbyl-gris-2'-ene-3,4'-dione.

7 EXAMPLE 9 A. 50 g. of the benzyl ether of 2-amino-3,5-dimethoxyphenolis addedto 100 ml. of methanol and 3 g. of 5% palladium on charcoal. Thesolution is treated with hydrogen until about 1 mole of hydrogen isconsumed. It is then filtered and concentrated to dryness in vacuo togive a residue of 2-amino-3,S-dimethoxyphenol.

20 g. of this phenol in 40 ml. of hydrochloric acid is mixed with 15 g.or" sodium, nitrite in 25 ml. of Water.

To the resulting solution is added 60 ml. of 40% fiuoboric acid. Adiazonium fluoborate salt precipitates and is recovered by filtration.It is Washed with fiuoboric acid and then successively with ethylalcohol and ether. It is then dried in vacuo. On Warming, the productdecomposes to give 2-fluoro-3,S-dimethoxyphenol which may be purified bydistillation in vacuo.

B. 2-fluoro 3,5 dimethoxyphenyl 2 methyl 4- acetoxy-6-methoxybenzoate isobtained by reacting together the acid chloride of2-methyl-4-acetoxy-6-methoxy benzoic acid and2-fiuoro-3,5-dirnethoxyphenol according to the procedure of Example 1A.This latter compound is hydrolyzed to2-fiuoro-3,S-dimethoxyphenyl-2-rnethyl- 4-hydroxy-6-methoxybenzoateaccording to the method of Example 1B.

When 2 fluoro 3,5 dimethoxyphenyl-Z-methyl-4- iydroxy-6-methoxyhenzoateis irradiated with ultraviolet light according to the process describedin Example 2, there is obtained 2,4 dihydroxy 3 fluoro 4,6,2trimethoxy-6'-methylbenzophenone. This latter material is converted withaqueous potassium carbonate and potassium ferricyanide .to racemic7-fluoro-4-,6,2'-trimethoxy- 6'-rnethyl-gris-2',5-diene-3,4-dione underthe conditions set forth in Example 3 above.

Racernic 7 fluoro 4,6,2 trimethoxy 6' methylgris-2-ene-3,4'-dione isobtained by hydrogenating a solution of the diene in the presence ofpalladium catalyst by the method of Example 4.

EXAMPLE 10 2,4 '-Dilzydr0xy-4,6,2'-T rimethoxy-fi-M ethyl-3Chloro-Benzophenone A. 1.0 g. of dehydrogriseofulvin in 100 ml. ofacetic acid is treated with stirring at room temperature With 4.0 g. ofzinc dust. The reaction mixture is allowed to stir at room temperaturefor 16 hours. The zinc is then removed by filtration and the filtrateconcentrated to dryness in vacuo. The residue is dissolved in methylenechloride and extracted four times with ice-cold 2% aqueous potassiumhydroxide. The yellow alkaline extracts are acidified with dilutesulfuric acid and the precipitated solid recovered by filtration. It isextracted with chloroform, and the chloroform extracts Washed with waterand dried over magnesium sulfate. The chloroform solution is filteredand concentrated to dryness in vacuo. The residue is crystallized fromacetone-benzene to give 720 mg. of2,4'-dihydroxy-4,6,2-trimethoxy-6'-methyl-3- chloro-benzophenone, M.P.210-212" C.; A max. 297 me (e, 18,500) and 332 m (6, 6,200).

B. To a solution of 100 mg. of dehydrogriseotulvin in ml. of acetic acidlayered with petroleum ether is added 4 ml. of an aqueous solution ofchromous chloride (4.0 mmole) and the reaction mixture is stirred atroom temperature for 16 hours. The green reaction mixture is thendiluted with a large volume of chloroform and Washed with cold aqueous2% sodium bicarbonate, cold dilute hydrochloric acid, water and driedover magnesium sulfate. Concentration of the chloroform solution invacuo affords, after crystallization from acetone-benzene, 41 mg. of2,4'-dihydroxy-4,6,2'-trimethoxy-6-rnethyl-3- chloro-benzophenone, M.P.2l0-212 C.

C. Substitution of chrornous acetate for chromous chloride in theprocedure of Fart B gives the same result.

EXAlviPLE l1 Dehydrogriseofulvin A suspension of 5.0 g. of griseoiulvinand 5.0 g. of freshly sublimed selenium dioxide in 250 ml. of t-butanolis rel uxed in a nitrogen atmosphere for 65 hours. After filtrationthrough diatomaceous earth, the reaction mixture is concentrated invacuo to an orange solid. The latter is dissolved in benzene and Washedthree times with Water, dried over magnesium sulfate, concentrated invacuo to a small volume and then chromatographed on 200 g. of Florisil.From the chloroform eluates there is obtained 2.09 g. ofdehydrogriseofulvin, M.P. 257- 258 C., after crystallization frombenzene. The melt crystallizes and remelts at 267-269 C.

Any departure from the above description which conforms to the presentinvention is intended to be included Within the scope of the claims.

What is claimed is:

1. The process for preparing a compound having the structural formulaWhere R is selected from the class consisting of hydrogen and halogen,and R is selected from the class consisting of hydrogen and lower alkylgroups, that comprises intimately contacting a compound of the formulawhere Rand B, have the meaning defined above, with a reducing agentselected from the class consisting of chromous chloride, chromousacetate, zinc-acetic acid and zinchydrochloric acid.

2. The process for preparing2,4-dihydroxy-4,6,2-trirnethoxy-6-methyl-3-ohloro-benzophenone thatcomprises intimately contacting 7 chloro 4,6,2-trimethoxy-6'-methyl-gris-Z',5'-diene-3,4-dione with zinc in the presence of aceticacid.

' References Cited in the file of this patent UNITED STATES PATENTS2,861,104 Von Glahn et a1 Nov. 18, 1958 2,861,105 Stanley et a1 Nov. 18,1958 2,879,275 Feichtinger et al. Mar. 24, 1959 2,881,187 Feichtinger eta1. Apr. 7, 1959

1. THE PROCESS FOR PREPARING A COMPOUND HAVING THE STRUCTURAL FORMULA